Lyme disease, a multisystem disorder due to the tick-transmitted spirochete Borrelia burgdorferi (Bb), is the most common vector-borne disease in the United States. Factors that influence the outcome from infection include genotype of the infecting spirochete, host immune responses, and use of antibiotics. Mammalian innate immune cells respond to proinflammatory Bb lipoproteins through tile Toll-like receptor family of pattern recognition receptors, all of which utilize the common adaptor protein MyD88 to initiate inflammation. MyD88-deficient mice infected with Bb exhibit uncontrolled pathogen growth in the face of strong humoral immune responses, yet develop disease identical to that seen in wild-type mice. This proposal will use MyD88-deficient mice to examine the role of innate irmmunity in tick acquisition and transmission of high and low infectivity Bb genotypes and the evolution of disease in the mouse relative to infecting spirochete genotype. Xenodiagnosis using ticks has previously been used to document the persistence of attenuated spirochetes after antibiotic treatment of Bb-infected mice, and spirochete DNA can be found in the joints as much as 1 year after treatment. A second goal of this proposal is to exploit the high pathogen burden of Bb-infected MyD88-deficient mice to 1) facilitate the molecular characterization of spirochetes that are retrieved by xenodiagnostic ticks after feeding on Bb-infected mice treated with antibiotics; 2) determine whether residual DNA in joints reflects persistent viable spirochetes through culture techniques as well as Bb gene expression microarrays; and 3) evaluate the utility of a combination oral antibiotic regimen in the elimination of Bb DNA from infected joints. The results of these studies will enhance our understanding of mammalian host factors that contribute to susceptibility to infection and disease, and may permit the identification of genes expressed by host-adapted spirochetes that can be used for establishment of diagnosis and/or efficacy of antibiotic therapy.